Muscular Dystrophy (MD) is a group of muscle disorders in which muscle fibers are unusually susceptible to damage. As a result, defects in muscle proteins accumulate, death of muscle cells and tissue occurs and the musculoskeletal system of affected individuals becomes progressively weaker. Nine major types of muscular dystrophy have been identified; Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, mytonic, oculopharyngeal, distal and Emery-Dreifuss muscular dystrophy. Several muscular dystrophy-like conditions have also been identified.
In normal striated muscle dystrophin associates with a large group of proteins known as the dystrophin glycoprotein complex (DGC) (1). The DGC serves to stabilise the sarcolemma by making regularly spaced connections between the muscle fibre cytoskeleton and extracellular matrix—part of the costameric cell adhesion complex (2). At the core of this cell adhesion complex is the adhesion receptor dystroglycan which binds laminin in the extracellular matrix and dystrophin on the cytoplasmic face (3). However, in a number of disorders, including the muscular dystrophies, generation of functional dystrophin protein and/or functional DGC is impaired.
Like many cell adhesion complexes, the DGC also has associated signalling activity. Tyrosine phosphorylation of dystroglycan has been identified as an important regulatory event in controlling the interaction between dystrophin and dystroglycan, and therefore plays an important role in maintaining the integrity of the DGC (4). Previous studies have shown that inhibition of the proteasome is able to restore other DGC components in both mdx mice that lack dystrophin and in explants of DMD patients (8, 9).
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease that affects approximately 1 in 3,500 male births and for which there is currently no cure or effective treatment. Various molecular genetic approaches to combat DMD have been devised but are unlikely to address the need of all DMD sufferers: gene replacement using a number of delivery methods, compensatory gene upregulation and cell based therapies have all met with some success in the laboratory but have failed for a variety of reasons to translate to the clinic (Pichavant. C, et al. Mol Ther, 2011). More recently, however, significant successes have been achieved using exon skipping approaches to splice out mutated parts of the DMD gene and restore some functional dystrophin gene (Kinali. M, et al Lancet Neurol., 2009. 8: 918). This is a rapidly developing area with phase II clinical trials of exon skipping in progress. These approaches provide real hope for the approximately 25% of DMD patients with no effective treatment. Clearly a therapeutic approach that could be effective for all DMD sufferers is still needed. Ideally, there is a need for a small molecule treatment which is simple to administer, does not require customisation to a particular individual, and is well tolerated with a good safety profile. Such a treatment does not currently exist.